ABSTRACT Patients with hypertension (HTN) are characterized by an exaggerated blood pressure response and premature fatigue during physical activities. An abnormal exercise pressor reflex (EPR) mediated by neural feedback from mechano- and/or metabosensitive group III and IV muscle afferents might contribute to these abnormalities. However, even in health, our understanding of the exact role and relative contribution of group III/IV afferents to the circulatory control and the development of fatigue during exercise is incomplete. By studying both HTN patients and well-matched healthy controls (CTRLs), we will evaluate the impact of HTN on the relative contribution of these muscle afferents to the circulatory control and the development of central and peripheral fatigue during exercise. The proposed studies will also examine the impact of HTN on muscle morphometry and contraction-induced intramuscular (whole muscle and muscle interstitium) metabolic changes, gene expression and protein levels of metabosensitive receptors on muscle afferents, and the functional impact of these changes in terms of fatigue. Specifically, we will use lumbar intrathecal fentanyl to block the central projection of group III/IV muscle afferents during voluntary and passive exercise (no concomitant effect on feedforward drive). This proven approach will enable us to evaluate and distinguish between the effects of group III and IV muscle afferents on blood pressure, leg blood flow, and cardiac output during large and small muscle mass exercise (bicycle and knee-extension), and the development of central and peripheral fatigue (femoral nerve stimulation techniques). We will also conduct morphometric and metabolite analysis on pre/post-exercise muscle biopsies and dialysate (resulting from intramuscular microdialysis during exercise) to evaluate alterations in intrinsic muscle characteristic as a potential factor determining metaboreflex abnormalities in HTN. Furthermore, we will determine the mRNA and protein levels of ASIC3, P2X, EP4 and TRPV1 receptors in human dorsal root ganglion neurons of HTN patients and CTRLs. Finally, to determine the specific contribution of these metabosensitive molecular receptors to the development of central fatigue in HTN and CTRLs, we will perform an intramuscular infusion of a metabolite soup into the unfatigued quadriceps muscle. We have designed the soup to specifically activate ASIC3, P2X, and TRPV1 receptors and have verified it's specificity in published animal and human studies. Based on recent findings suggesting greater metaboreceptor-mediated reflexes in HTN vs CTRLs, we expect, following the intramuscular soup infusion, greater central fatigue in HTN vs CTRLs. The results from this analysis will contribute to a better understanding of the role of metaboreceptors as a potential mechanism underlying central fatigue and reflex abnormalities characterizing exercising HTN patients. Combined, this research will provide new insight into the impact of HTN on the EPR and group III and IV- mediated afferent feedback and associated consequences for the neuro-circulatory response and fatigue during physical activities.